Experience-Dependent Reorganization of Excitatory Synapse Connectivity

神经精神障碍的压倒性遗传证据表明兴奋性突触和 可塑性组件，对于依赖经验的神经电路优化至关重要。这导致了 一种假说认为，经验依赖型发育可塑性的失调是由 分子和细胞缺陷会导致行为异常。因此，必须了解如何 经验塑造了兴奋性突触在发育过程中的功能联系；以及在 病理条件下，这种受损的机制使正常的发育轨迹脱轨。使用 以小鼠初级视皮层(V1)为模型系统，我们发现在功能成熟过程中 在兴奋性突触中，AMPA受体介导的突触传递在 关键时期。这种平衡的维持需要神经颗粒素(Ng)，一种突触后钙调蛋白 (CaM)结合蛋白对突触可塑性很重要，与精神分裂症和精神分裂症有关 智力迟缓。两种拮抗机制，经验依赖的AMPAR-沉默突触转换和 依赖经验的突触消除，依赖于Ng在 关键时期。我们的初步研究表明，降低Ng水平会导致发育转换延迟 N-甲基-D-天冬氨酸受体亚单位的改变，以及神经元磷酸化特征的改变。我们假设吴昌俊 通过控制钙/钙调素调节兴奋性突触连接的经验依赖性组织 依赖的磷酸酶活性，它决定了突触NMDAR的组成和活性 发展(与精神分裂症相关的关键组成部分)。使用病毒介导的组合 基因操作、电生理学、形态分析和行为审问，我们将阐明 支配经验依赖的兴奋性突触连接细化的分子途径 在发育过程中，对感官知觉至关重要。我们的研究将有助于理解分子 对健康和疾病的钙稳态很重要的机制，并可能提供治疗 精神分裂症患者药物干预的底物。

Overwhelming genetic evidence in neuropsychiatric disorders points towards the excitatory synapse and plasticity components, essential for experience-dependent optimization of the neural circuit. This leads to the hypothesis that dysregulation in experience-dependent developmental plasticity caused by the molecular and cellular deficit leads to behavioral abnormalities. It is therefore essential to understand how experience sculpts the functional connection of excitatory synapses during development; and how under the pathological condition, this impaired mechanism derails the normal developmental trajectory. Using the mouse primary visual cortex (V1) as the model system, we have shown that during the functional maturation of excitatory synapses, AMPA receptor-mediated synaptic transmission remains at equilibrium during the critical period. The maintenance of this equilibrium requires neurogranin (Ng), a postsynaptic calmodulin (CaM)-binding protein important for synaptic plasticity, which is associated with schizophrenia and mental retardation. Two antagonizing mechanisms, experience-dependent AMPAR-silent synapse conversion and experience-dependent synapse elimination, hinge upon Ng for constructive synaptic refinement during the critical period. Our preliminary studies show that decreasing Ng levels led to delayed developmental switch of the NMDA receptor subunits, and shift in neuronal phosphorylation profiles. We hypothesize that Ng regulates experience-dependent organization of excitatory synaptic connectivity via controlling Ca/CaM- dependent phosphatase activities, which determine synaptic NMDAR composition and activity during development (critical components associated with schizophrenia). Using a combination of virus-mediated gene manipulation, electrophysiology, morphological analysis and behavioral interrogation, we will elucidate the molecular pathways governing experience-dependent refinement of excitatory synaptic connectivity during development, essential for sensory perception. Our study will help understand the molecular mechanisms important for calcium homeostasis in health and diseases, and may provide therapeutic substrate for pharmacological interventions for schizophrenia patients.